Pathophysiology of Adult T-cell Leukemia/Lymphoma

成人 T 细胞白血病/淋巴瘤的病理生理学

• 批准号: 10045553
• 负责人: Utpal P Dave
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-03 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045553
• 关键词: Acute T Cell Leukemia; Adult T-Cell Leukemia/Lymphoma; Advanced Development; Affect; Age Distribution; Apoptosis; Biological Markers; Bone Marrow; Caring; Chemotherapy-Oncologic Procedure; Clinical; Cytokine Activation; Cytokine Signaling; Cytotoxic agent; DNA Sequence Alteration; Data; Development; Disease; Elderly; FDA approved; FLT3 gene; Female; Fibrinogen; Foundations; Functional disorder; Gene Expression Profiling; Genes; Genetic Transcription; Health; Hematologic Neoplasms; Human; IL2RG gene; JAK1 gene; JAK3 gene; LMO2 gene; Laboratories; Lymphocyte Function; Lymphoma; Mutate; Mutation; Myeloid Leukemia; Neoplasms; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Proteins; RUNX1 gene; Resistance; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stat5 protein; Stimulus; T-Cell Development; T-Cell Leukemia; T-Cell Transformation; T-Cell and NK-Cell Neoplasm; T-Lymphocyte; Testing; Transgenic Mice; Transplantation; Tumor stage; Veterans; Work; base; chemotherapy; driver mutation; drug sensitivity; experience; gain of function; in vivo; inhibitor/antagonist; knock-down; leukemia; leukemia/lymphoma; leukemogenesis; male; military veteran; mouse model; mutant; new therapeutic target; novel marker; novel therapeutic intervention; overexpression; precision medicine; progenitor; protein complex; refractory cancer; self-renewal; stem cells; synergism; targeted biomarker; targeted treatment; therapeutic target; transcription factor; tumor initiation; young adult

T-cell leukemias and lymphomas are clinically aggressive cancers resistant to conventional chemotherapy regimens and in desperate need for novel therapeutic approaches. This proposal studies the pathogenesis of these hematologic neoplasms and directly benefits Veterans' health by advancing the development of targeted therapy, and precision medicine for these treatment-resistant cancers. Our laboratory has been studying T-cell neoplasms from the perspective of two major oncogenic pathways: the LIM domain Only-2 (LMO2) pathway and the IL2RG/JAK1/3/STAT5 cytokine signaling pathway. LMO2 is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia. LMO2 encodes a small 18 kDa protein that is part of a large multisubunit protein complex that regulates the transcription of key target genes. We have been dissecting the mechanism by which LMO2's enforced expression induces T-ALL and have discovered key pre-leukemic phenotypes enforced by LMO2 like differentiation arrest and enhanced self-renewal. The IL2RG/JAK1/3/STAT5 pathway is required for the development and function of lymphocytes and our lab discovered that gain of function in this pathway is common in both mature and immature T-cell neoplasms. In recent exciting data, our LMO2 and JAK3 work has converged in intriguing findings. Mutational and gene expression analyses show that LMO2 overexpression and JAK3 activating mutations are concordant hits in both mature and immature T-cell neoplasms. The results imply that these two pathways cooperate to induce T- cell transformation. Interestingly, enforced expression of LMO2 in double negative T-cell progenitors induces highly penetrant T-cell leukemias but double positive progenitors do not develop leukemia. Similarly, enforced expression of constitutively active mutant JAK3 does not induce disease on its own. We hypothesize that T-cell transformation into leukemia or lymphomas may manifest if these two pathways were concordantly activated. In this proposal, we will investigate the mechanistic basis of this cooperativity so that T-cell leukemias and lymphomas may be better targeted therapeutically. In Aim 1, we will investigate the cooperativity between LMO2 and JAK3 oncogenes using bone marrow transduction and transplantation in our Lmo2 transgenic mouse model. In Aim 2, we will analyze signal transduction within the IL2RG/JAK1/3/STAT5 pathway in leukemias and lymphomas induced in Lmo2 transgenic mice. In Aim 3, we will test the use of JAK inhibitors against primary human T-cell neoplasms and analyze synergy with chemotherapy and LMO2 knockdown. The Aims will establish a foundation for the development of novel biomarkers and novel therapeutic approaches based on LMO2 and IL2RG/JAK1/3/STAT5 pathways.

T 细胞白血病和淋巴瘤是对传统化疗耐药的临床侵袭性癌症 方案并迫切需要新的治疗方法。本提案研究了发病机制 这些血液肿瘤，并通过促进有针对性的开发直接有益于退伍军人的健康 针对这些难治性癌症的治疗和精准医学。我们实验室一直在研究T细胞 从两个主要致癌途径的角度来看肿瘤：LIM结构域Only-2（LMO2）途径 和 IL2RG/JAK1/3/STAT5 细胞因子信号通路。 LMO2 是最常放松管制的一种 T 细胞急性淋巴细胞白血病中的癌基因。 LMO2 编码一个 18 kDa 的小蛋白，该蛋白是大蛋白的一部分 调节关键靶基因转录的多亚基蛋白质复合物。我们一直在剖析 LMO2 强制表达诱导 T-ALL 的机制，并发现了关键的白血病前期 LMO2 强制执行的表型包括分化停滞和自我更新增强。这 IL2RG/JAK1/3/STAT5 通路是淋巴细胞的发育和功能所必需的，我们的实验室 发现该途径的功能获得在成熟和未成熟 T 细胞肿瘤中都很常见。在 最近令人兴奋的数据，我们的 LMO2 和 JAK3 工作得出了有趣的发现。突变和基因 表达分析表明，LMO2 过表达和 JAK3 激活突变在 成熟和未成熟的 T 细胞肿瘤。结果表明这两条途径协同诱导 T- 细胞转化。有趣的是，LMO2 在双阴性 T 细胞祖细胞中的强制表达诱导 高渗透性 T 细胞白血病，但双阳性祖细胞不会发展为白血病。同样，强制 组成型活性突变体 JAK3 的表达本身不会诱发疾病。我们假设 T 细胞 如果这两条途径一致激活，则可能会转化为白血病或淋巴瘤。 在本提案中，我们将研究这种协同作用的机制基础，以便 T 细胞白血病和 淋巴瘤可能有更好的治疗目标。在目标 1 中，我们将研究之间的协作性 在我们的 Lmo2 转基因中使用骨髓转导和移植的 LMO2 和 JAK3 癌基因 鼠标模型。在目标 2 中，我们将分析 IL2RG/JAK1/3/STAT5 通路内的信号转导 Lmo2 转基因小鼠诱发白血病和淋巴瘤。在目标3中，我们将测试JAK抑制剂的使用 对抗原发性人类 T 细胞肿瘤并分析与化疗和 LMO2 敲低的协同作用。这 目标将为新型生物标志物和新型治疗方法的开发奠定基础 基于 LMO2 和 IL2RG/JAK1/3/STAT5 途径。